Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Our aim was to determine if sympathetic vasodilatation occurs in the human forearm, and if the vasodilating substance nitric oxide contributes to this dilatation. We also sought to determine if the nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium. 2. Blood flow was measured in the resting non-dominant forearm with venous occlusion plethysmography. To increase sympathetic traffic to the resting forearm, rhythmic handgrip exercise to fatigue followed by post-exercise ischaemia was performed by the dominant forearm. A brachial artery catheter in the non-dominant arm was used to selectively infuse drugs. 3. During control conditions, there was mild vasodilatation in the resting forearm during exercise followed by constriction during post-exercise ischaemia. When exercise was performed after brachial artery administration of bretylium (to block noradrenaline release) and phentolamine (an alpha-adrenergic antagonist), profound vasodilatation was seen in the resting forearm during both exercise and post-exercise ischaemia. 4. When the nitric oxide synthase blocker NG-monomethyl-L-arginine (L-NMMA) was administered in the presence of bretylium and phentolamine prior to another bout of handgripping, little or no vasodilatation was seen either during exercise or post-exercise ischaemia. Atropine also blunted the vasodilator responses to exercise and post-exercise ischaemia after bretylium and phentolamine. 5. These results support the existence of active sympathetic vasodilatation in the human forearm and the involvement of nitric oxide in this phenomenon. They also suggest nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium.
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PMID:Evidence for nitric oxide-mediated sympathetic forearm vasodiolatation in humans. 903

1. We studied the mechanism of insulin-mediated attenuation of noradrenaline-induced vasoconstriction in mesenteric resistance arteries (approximately 210 microns diameter) from 10-week-old male Wistar rats (n = 10; weight 321 +/- 11 g). Exposure to physiological concentrations of insulin (50 m-units/l) significantly blunted the contractile response to noradrenaline over the concentration range 3 x 10(-6) to 3 x 10(-5) mol/l (16 vessels; 13.1 +/- 4.3% reduction in maximum tension at 3 x 10(-5) mol/l noradrenaline; P < 0.01 versus no insulin). 2. This effect of insulin was prevented by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10(-4) mol/l; 16 vessels; 3.3 +/- 9.1% reduction in maximum tension; P = 0.8 versus no insulin). There was no evidence of fatigue in four noradrenaline dose-response curves for 16 control vessels in the absence of insulin and NG-nitro-L-arginine methyl ester (P = 0.8; first versus second dose-response curve). With L-arginine present in the incubation medium, insulin again attenuated the noradrenaline-induced vasoconstriction (10.7 +/- 3.2% reduction in tension; P = 0.02 versus L-arginine and no insulin; P = not significant versus insulin and no L-arginine). 3. Endothelium-dependent relaxation was initially confirmed in all vessels by demonstrating normal acetylcholine- (5.4 x 10(-7) to 1.1 x 10(-4) mol/l) induced vasodilatation in vessels preconstricted with noradrenaline (6 x 10(-6) mol/l) in the absence of NG-nitro-L-arginine methyl ester, L-arginine and insulin (P = not significant between the different groups of vessels). 4. We conclude that insulin attenuates noradrenaline-induced vasoconstriction in resistance arteries by stimulation of nitric oxide release. Abnormal insulin-stimulated nitric oxide release could be of relevance in the pathogenesis of hypertension and diabetic microvascular disease.
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PMID:Insulin-induced attenuation of noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent. 905 15

The role of endogenous nitric oxide (NO) in producing diaphragmatic fatigue was examined in 26 anaesthetized, mechanically ventilated dogs divided into four groups. In Group Ia (n = 5), dogs without fatigue received only Ringer's lactate solution. In Group Ib (n = 5), dogs without fatigue were given i.v. L-arginine analog N omega-nitro-L-arginine methyl ester (L-NAME) 10 mg.kg-1 to inhibit NO synthase (NOS). Groups IIa and IIb (n = 8 of each) received the same doses of i.v. lactate and L-NAME as Groups Ia and Ib effectively. Following administration of the i.v. solution, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Diaphragmatic contractility was assessed in each group by measuring transdiaphragmatic pressure (Pdi). No difference in Pdi was observed between Groups Ia and Ib. After the fatigue-producing period, in Group IIa, Pdi at low-frequency (20 Hz) stimulation decreased from the pre-fatigued values (P < 0.05), whereas Pdi at high-frequency (100 Hz) stimulation did not change. In Group IIb, given L-NAME before producing fatigue, Pdi at both stimuli did not change. In conclusion, L-NAME inhibits the production of diaphragmatic fatigue. This finding suggests that endogenous NO plays an important role in producing diaphragmatic fatigue.
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PMID:Protection from diaphragmatic fatigue by nitric oxide synthase inhibitor in dogs. 2357 74

Skeletal muscle constitutively expresses both the type I (neuronal) and type III (endothelial) isoforms of nitric oxide synthase (NOS). We tested the functional importance of type III NOS using skeletal muscles with similar levels of type III NOS expression (diaphragm and soleus) from wild-type, heterozygous, and type III NOS-deficient littermate mice. Muscles were incubated at 37 degrees C in Krebs-Ringer solution. NO accumulation in the medium was measured by chemiluminescence; force-frequency and fatigue characteristics were measured using direct electrical stimulation. Diaphragm and soleus released NO at similar rates during passive incubation; these rates increased during active contraction. NO release by type III NOS-deficient muscle was not different from that of wild-type muscle under any condition tested. Force-frequency and fatigue characteristics also were unaffected by genotype. Because type III NOS deficiency did not alter function, we conclude that NO effects previously observed in wild-type muscle are likely to be mediated by type I NOS.
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PMID:Nitric oxide release and contractile properties of skeletal muscles from mice deficient in type III NOS. 1064 26

Extraocular muscles (EOMs) are specialized skeletal muscles that are constantly active, generate low levels of force for cross sectional area, have rapid contractile speeds, and are highly fatigue resistant. The neuronal isoform of nitric oxide synthase (nNOS) is concentrated at the sarcolemma of fast-twitch muscles fibers, and nitric oxide (NO) modulates contractility. This study evaluated nNOS expression in EOM and the effect of NO modulation on lateral rectus muscle's contractility. nNOS activity was highest in EOM compared with diaphragm, extensor digitorum longus, and soleus. Neuronal NOS was concentrated to the sarcolemma of orbital and global singly innervated fibers, but not evident in the multi-innervated fibers. The NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor), increased submaximal tetanic and peak twitch forces. The NO donors S-nitroso-N-acetylcysteine (SNAC) and spermineNONOate reduced submaximal tetanic and peak twitch forces. The effect of NO on the contractile force of lateral rectus muscle is greater than previously observed on other skeletal muscle. NO appears more important in modulating contraction of EOM compared with other skeletal muscles, which could be important for the EOM's specialized role in generation of eye movements.
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PMID:Nitric oxide synthase expression and effects of nitric oxide modulation on contractility of rat extraocular muscle. 1148 Dec 24

Nitric oxide (NO) is essential for optimal myofilament function of the rat diaphragm in vitro during active shortening. Little is known about the role of NO in muscle contraction under hypoxic conditions. Hypoxia might increase the NO synthase (NOS) activity within the rat diaphragm. We hypothesized that NO plays a protective role in isotonic contractile and fatigue properties during hypoxia in vitro. The effects of the NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA), the NO scavenger hemoglobin, and the NO donor spermine NONOate on shortening velocity, power generation, and isotonic fatigability during hypoxia were evaluated (Po(2) approximately 7 kPa). l-NMMA and hemoglobin slowed the shortening velocity, depressed power generation, and increased isotonic fatigability during hypoxia. The effects of l-NMMA were prevented by coadministration with the NOS substrate l-arginine. Spermine NONOate did not alter isotonic contractile and fatigue properties during hypoxia. These results indicate that endogenous NO is needed for optimal muscle contraction of the rat diaphragm in vitro during hypoxia.
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PMID:Effects of modulation of nitric oxide on rat diaphragm isotonic contractility during hypoxia. 1239 Nov 24

In anaesthetised rats, Fos-immunoreactive and NADPH-diaphorase-positive neurons in the medulla and, for comparison, in the spinal cord were studied after fatiguing stimulation of the hindlimb muscles. Following both direct muscle stimulation and L5 ventral root stimulation, fatigue-related c-fos gene expression was most prominent in the dorsal horn of the ipsilateral L2-L5 segments and within the ipsilateral nucleus tractus solitarius, the caudoventrolateral and rostroventrolateral reticular nuclei, and the intermediate reticular nucleus at levels of -14.3 and -13.8 mm, and contralaterally at -13.2 mm caudal to the bregma. The order of intensity of c-fos expression was as follows: nucleus tractus solitarius>caudoventrolateral and rostroventrolateral reticular nuclei>intermediate reticular nucleus>lateral paragigantocellular nucleus. NADPH-diaphorase reactivity was changed in the following sequence: NTS>intermediate reticular nucleus lateral paragigantocellular nucleus>rostroventrolateral reticular nucleus. Fos-immunoreactive neurons were codistributed with NADPH-diaphorase-reactive cells within the dorsomedial and ventrolateral medulla, and double-staining neurons were found in the nucleus tractus solitarius, intermediate reticular nucleus and lateral paragigantocellular nucleus. The patterns of distribution of c-fos expression and NADPH-diaphorase reactivity show that afferent signals arising from fatiguing muscles may activate spinal and medullary neurons which are involved in nociceptive and cardiovascular reflex pathways. The functional role of nitric oxide (NO) in the generation of cardiovascular and somatosensory responses in the medulla during fatigue of skeletal muscles is discussed.
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PMID:NADPH-diaphorase activity and c-fos expression in medullary neurons after fatiguing stimulation of hindlimb muscles in the rat. 1246 54

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC(50) = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 microM), tetanus toxin (1 microM), P/Q/N type-calcium channel blockers (1 microM omega-agatoxin IVA and 1 microM omega-conotoxin GIVA) and bafilomycin A(1) (1 microM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.
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PMID:HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway. 1586 Jun 48

Nitric oxide (NO) has an inhibitory action on O2 uptake (VO2) at the level of the mitochondrial respiratory chain. The aim of this study was to evaluate the effects of NO synthase (NOS) inhibition on muscle (VO2) kinetics. Isolated canine gastrocnemius muscles in situ (n = 6) were studied during transitions from rest to 4-min of electrically stimulated contractions corresponding to approximately 60% of the muscle peak . Two conditions were compared: (i) Control (CTRL) and (ii) L-NAME, in which the NOS inhibitor L-NAME (20 mg kg(-1)) was administered. In both conditions the muscle was pump-perfused with constantly elevated blood flow (Q), at a level measured during a preliminary contraction trial with spontaneous self-perfused (Q). A vasodilatory drug was also infused. Arterial and venous O2 concentrations were determined at rest and at 5-7 s intervals during the transition. VO2 was calculated by Fick's principle. Muscle biopsies were obtained at rest and during contractions. Muscle force was measured continuously. Phosphocreatine hydrolysis and the calculated substrate level phosphorylation were slightly (but not significantly) lower in L-NAME than in CTRL. Significantly (P < 0.05) less fatigue was found in L-NAME versus CTRL. The time delay (TD(f)) and the time constant (tau(f)) of the 'fundamental' component of VO2 kinetics were not significantly different between CTRL (TD(f) 7.2 +/- 1.2 s; and tau(f) 10.6 +/- 1.3, +/- s.e.m.) and L-NAME (TD(f) 9.3 +/- 0.6; and tau(f) 10.4 +/- 1.0). Contrary to our hypothesis, NOS inhibition did not accelerate muscle VO2 kinetics. The down-regulation of mitochondrial respiration by NO does not limit the kinetics of adjustment of oxidative metabolism at exercise onset.
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PMID:Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ. 1675 29

To assess the role of nitric oxide (NO) in central thermoregulatory mechanisms during exercise, 1.43 micromol (2 microL) of N(omega)-nitro-L-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microL of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18 m min(-1), 5% inclination). Core (Tb) and skin tail (Ttail) temperatures were measured. Body heating rate (BHR), threshold Tb for tail vasodilation (TTbV), and workload (W) were calculated. During the first 11 min of exercise, there was a greater increase in Tb in the L-NAME group than in the SAL group (BRH=0.17+/-0.02 degrees C min(-1), L-NAME, versus 0.09+/-0.01 degrees C min(-1), SAL, p<0.05). Following the first 11 min until approximately 40 min of exercise, Tb levels remained stable in both groups, but levels remained higher in the L-NAME group than in the SAL group (39.16+/-0.04 degrees C, L-NAME, versus 38.33+/-0.02 degrees C, SAL, p<0.01). However, exercise went on to induce an additional rise in Tb in the SAL group prior to fatigue. These results suggest that the reduced W observed in L-NAME-treated rats (10.8+/-2.0 kg m, L-NAME, versus 25.0+/-2.1 kg m, SAL, p<0.01) was related to the increased BHR in L-NAME-treated animals observed during the first 11 min of exercise (r=0.74, p<0.01) due to the change in TTbV (39.12+/-0.24 degrees C, L-NAME, versus 38.27+/-0.10 degrees C, SAL, p<0.05). Finally, our data suggest that the central nitric oxide pathway modulates mechanisms of heat dissipation during exercise through an inhibitory mechanism.
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PMID:Nitric oxide pathway is an important modulator of heat loss in rats during exercise. 1614 Jan 69


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